Camptothecin is a well-known naturally occurring compound which was discovered to possess antineoplastic properties by Wall and Wani in the early 1960s. Efforts have been made since then to improve upon the anti-proliferative properties of Camptothecin and its analogues, and to reduce the unwanted toxicities of this series of agents.
Camptothecin and many of its analogues are very poorly soluble in water. Many such analogues exhibit water solubility of less than five micrograms per milliliter. This poor water solubility originally presented problems of administration of the intended drug, and early efforts were devoted to making the drug practical for administration to human patients.
These early efforts involved the formulation of Camptothecin analogues with sodium hydroxide, in which the compounds were readily soluble. Unfortunately, these formulations caused the opening of the lactone `E` ring of the analogue, which resulted in both reduced antineoplastic activity and higher unwanted toxicity upon administration.
Another avenue of exploration has been the development of Camptothecin analogues, which exhibited improved water solubility. Compounds which have resulted from this research include the FDA approved drugs Irinotecan (Camptosar.RTM., CPT-11) and Topotecan (Hycamptin.RTM.), as well as other analogues in clinical trials and under development.
Improving the water solubility of Camptothecin analogues improves the ease of administration of the drug to patients. However, especially in the case of Irinotecan, the compound is administered is a pro-drug which requires activation in vivo to the hydrophobic active species (SN38). And none of the water soluble analogues developed thus far has dealt with the problem of unwanted toxicity, thought to be mediated in part by the in vivo glucuronidation of the Camptothecin scaffold. Also, these water soluble derivatives are rapidly converted from the active `E` ring lactone form to the inactive and toxic carboxylate form in plasma.
The inventors of the present application have directed recent efforts in discovering and developing analogues of Camptothecin which are poorly water soluble. Several of these analogues are disclosed in U.S. patent application Ser. Nos. 08/914,207, filed Aug. 17, 1997, and 09/022,310, filed Feb. 11, 1998.
Poorly water soluble Camptothecin analogues are formulated for administration with suitable solvents such as those disclosed in U.S. Pat. Nos. 5,726,181; 5,447,936; 5,468,754; and others referred to in the Information Disclosure Sheet which accompanies this application. Preferred solvents for these poorly water soluble Camptothecin analogues include dimethylacetamide (DMA), dimethylisosorbide (DMI) and N-methylpyrrolidinone (NMP).
The poorly water soluble Camptothecin analogues generally provide increased lactone stability and greater antitumor activity than the water soluble analogues. Some analogues also provide decreased potential for glucuronidation, which is the form most frequently associated with the unwanted toxicities of Camptothecin analogues.
In recent years it has been recognized that a common problem with many of the camptothecin analogues in clinical use is the low physiologic concentration of the drug in the active lactone form. It is well established that the lactone E-ring is correlated with antitumor activity and the open ring carboxylate form is correlated with both unwanted toxicity and a loss of antitumor activity.
When compared to the water soluble camptothecins, the reported concentrations of the lactone species are substantially higher (in mice) for SN38, 9-amino camptothecin, 9-nitro camptothecin and camptothecin. The low levels of lactone species in human plasma are thought to have a major effect in reducing the antitumor activity of camptothecins containing the commonly recognized 20(S) lactone E-ring moiety. It is reasonable to consider that if it were possible to increase the plasma concentration of the lactone species that the maintenance of higher concentrations of the lactone species of a camptothecin would generally result in a relative increase in the antitumor activity of the camptothecins in humans. This invention addresses this key concept and additionally enhances tissue penetration and bioavailability by increasing or maintaining lipophilic nature of the camptothecin molecule.